Lung cancer is the leading cause of cancer death in women and men in the U.S. It is estimated that there will be more than 230,000 patients diagnosed with lung cancer this year, with more than 160,000 deaths, and non-small cell lung cancer (NSCLC) will account for more than three quarters of these cases (1). Survival rates of NSCLC, the predominant type of lung cancer are unacceptably low, and new approaches to treat and prevent this disease are urgently needed.
The poor prognosis of advanced non-small cell lung cancer (NSCLC) is due, in part, to emergence of tumor resistance to chemotherapy (1). Recent data indicate that human tumors contain a small subset of cancer stem cells (CSC) responsible for drug resistance and tumor maintenance (2-5). If such minute subsets of CSC drive tumor formation and drug resistance, therapies targeting the bulk tumor mass but not CSC may fail.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with development of hamartomatous lesions in many organs (71-74). Some lesions grow progressively and require clinical intervention. TSC is due to mutations in either TSC1 or TSC2 genes. TSC1 (hamartin)/TSC2 (tuberin) protein complexes serve a critical role in negatively regulating mTOR complex 1 (mTORC1) which exerts downstream effects on cell transcription, translation, metabolism and proliferation. mTORC1 is constitutively active in cells lacking either TSC1 or TSC2 and in hamartomas of TSC patients. New therapeutic approaches to control the growth of TSC-related proliferative diseases are urgently needed.
Breast cancer is a worldwide health concern with about 1,000,000 million new cases each year. In the clinic, endocrine therapy is an important intervention in women with breast cancers that express estrogen receptor (ER), and treatment with tamoxifen has enhanced patient survival. The success of endocrine therapy is dependent on tight regulation of breast cell growth by steroids and growth factor receptors (27) most patients eventually stop responding to anti-estrogen therapy. Resistance to tamoxifen (TAM) and aromatase inhibitors represents a major drawback to treatment of hormone-dependent breast cancer, and new options for endocrine therapy are urgently needed to reverse this outcome (28-30).
At diagnosis, about 70% of breast cancer patients have tumors that express estrogen receptors (ER) and/or progesterone receptors (PR). Patients with ER+ tumors can be treated with hormonal therapy such as tamoxifen which was the first effective targeted therapy for breast cancer. However, all advanced ER+ tumors eventually develop endocrine resistance, and there is an urgent need for new interventions to stop endocrine resistance.
Subversion of growth factor receptors often occurs in malignancy, and members of the HER family are often implicated in cancer (31). Overexpression of HER-2 or related HER receptors occurs in two-thirds of sporadic breast tumors, while HER-2 over-expression/amplification is found in 25-30% of breast cancers (30-33), is generally a marker of poor prognosis (7), and it associates with failure of antiestrogen therapy in the clinic (28, 34-38, 69-72). It is generally held that biologic activity of estrogen in breast cells is mediated by its binding with high-affinity ER in the nucleus (27, 39).
Two systems that transmit extracellular signals into the machinery of the cell nucleus are the signaling pathways that activate nuclear factor κB (NF-κB) and estrogen receptor (ER). These two transcription factors induce expression of genes that control cell fates, including proliferation and cell death (apoptosis). Estrogen receptor (ER) and nuclear factor-kappaB (NFκB), a major regulator of pathways central to malignant progression, are known to be mutually inhibitory at several molecular levels. Some ER-positive breast cancers SERMS such as tamoxifen may stimulate cell growth and survival (62). Recent investigations elucidated a previously unsuspected effect of ER (63).
The aromatic plant known as feverfew (Tanacetum parthenium) contains a family of compounds known as sesquiterpene lactones, particularly parthenolide. Disclosed herein, inter alia, are solutions to these and other problems in the art.